Happy New Year! It's the beginning of another year in this digital age where science and technology continue to advance with leaps and bounds. And one can't help but ask, what awaits pharma in 2013? 

In answer to that question, we are confronted with various challenges in our individual projects and the evolving macro-environment of the industry. As an ex-scientist at the School of Pharmacy, University of London, where I earned a doctorate in pharmaceutics and drug delivery, I can fully appreciate the technical aspects involved in working to resolve problems in solubility and bioavailability, finding ways to enhance the delivery of therapeutics to targeted sites without causing detrimental effects on healthy cells, and developing stable formulations with favourable pharmacokinetic profiles. The real challenge, however, is resolving these issues in an increasingly cost-constrained marketplace.  

There is an escalating demand for medicines that are not only safe and effective, but that are also of good value, especially now that healthcare payers and governments have begun putting pricing pressure and cost constraints on new therapies. R&D pipelines, however, appear to be running dry with innovation on the decline and productivity hitting a plateau during the past decade. Drug development has evolved into a long and hard journey that is both costly and risky as we hear of more drugs failing in Phase III. On top of that, the industry is forced to confront its nemesis, the patent cliff, which sees blockbusters trampled by fiercely competitive generic drugs. 			

Yet, despite the gloomy outlook, the global pharmaceutical market is growing at a steady pace, even under such unfavourable economic circumstances. Sales reached $1.08 trillion in 2011 and, although the figures for 2012 have not yet been released, Business Monitor International projects that the market for medicines could be worth nearly $1.60 trillion by 2020. Indeed, pharma has proven its resilience time and time again, and should be commended for overcoming the many obstacles hurled at it, from tighter regulations and healthcare reforms, to more challenging market conditions and rising customer expectations. As an industry, it is still regarded as one of the strongest and wealthiest players of the global economy.  

 is committed to bringing you the latest trends and developments that shape the changing landscape of the global pharma industry, whether it's the rise of biologics, the new era of generics or advances in drug delivery, formulation and testing. So bring it on, 2013! 

Articles

Happy New Year! It's the beginning of another year in this digital age where science and technology continue to advance with leaps and bounds. And one can't help but ask, what awaits pharma in 2013?

Pharma Never Dies

Regulatory science underpins innovation and practices in drug manufacturing. The most common definition of 

 is a discipline that creates new tools, standards and approaches for use in assessing the safety, effectiveness, quality and performance of products. 

 Dan Ward/Le Club Symphonie/Ian Nolan/Getty Images			

In October 2010, FDA issued a framework for advancing regulatory science for public health, which focused on the following: accelerating delivery of new medical treatments; improving paediatric and children's health; protecting against emerging infectious diseases and terrorism; enhancing safety and health through informatics; protecting the food supply; modernising safety testing; meeting challenges for regulating tobacco; and setting a collaborative implementation framework. 

Following that framework, in August 2011, the agency released a strategic plan for advancing regulatory science at FDA, largely focused on science-based decision-making to improve public health. Part of this initiative identifies specific standards, methods and questions for drug reviewers to use in their review process. The overall effort builds upon the agency's Critical Path Initiative, launched in 2004, to drive innovation in scientific processes, which includes the 2011 report that prioritised eight areas, which included support for new approaches to improve product manufacturing and quality.  

FDA has launched several Centres for Excellence in Regulatory Science and Innovation (CERSI) to carry out these priorities. The agency's initiative in regulatory science was also enhanced with the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012. Section 1124 of FDASIA calls for improving medical product decision-making through guidance documents and the adoption of tools, methods, and processes. The US Health and Human Services (HHS) Secretary must issue performance reports on these goals for fiscal years (FY) 2014 and 2016. 

) spoke to FDA about these issues in a special interview on the future of bio/pharmaceutical regulation. 

PTE: In August 2011, FDA released a strategic plan, Advancing Regulatory Science at FDA. Priority 3 of that plan focuses on product manufacturing and quality, including enabling the development and evaluation of novel and improved manufacturing methods to improve product quality, namely through continuous manufacturing, novel manufacturing technologies, excipients and complex dosage forms, and process analytical technology (PAT) and quality-by-design (QbD) approaches. What does FDA and the industry hope to gain by focusing on these areas? 

 FDA is responsible for protecting the consumer through the availability of quality products. These approaches focus on good, sound science in achieving a high quality product. By applying QbD and understanding the role of excipients and complex dosage forms, a higher level of product and process understanding will be obtained. The other approaches, (PAT, continuous manufacturing and novel manufacturing technologies) utilise that understanding to achieve a more robust and capable manufacturing processes, resulting in higher product quality. With this higher level of product quality, the product failure rate is expected to drop, which in turn, will increase product availability, and reduce product cost. Therefore, by focusing on these science-based approaches, FDA is confident that the overall quality of pharmaceutical products [will] continue to increase. 

Modernising manufacturing approaches for pharmaceuticals, such as through QbD, continuous manufacturing and/or PAT, has the potential to benefit industry, regulators, and patients. Already, there have been multiple reports of quality and cost benefits to manufacturers through the use of QbD and/or PAT approaches. For patients, these approaches can lead to increased assurance of quality and product availability. For regulators, it potentially means less regulatory oversight postapproval due to regulatory flexibility (e.g., design space) filed with the application. FDA is currently pursuing additional pathways to ease postapproval changes for well-understood and controlled processes under a robust quality system. 

Continuous manufacturing, although new to most pharmaceutical manufacturing, is a commonly used technology in food and chemical processing. As more companies are gaining experience with continuous manufacturing, benefits are emerging, including cases of reduced manufacturing scale-up issues, reduced material usage in development, and flexible manufacturing capacities. Because of the changing dynamics of new drugs toward more specialised, lower-volume products, continuous manufacturing could become more commonplace in the years ahead. 

Finally, it is becoming increasingly important to understand the interactions between drug(s), excipients, and device components as pharmaceutical dosage forms are becoming more complex, such as multiple active ingredients in a single drug product or drug–device combinations. The higher level of understanding should allow for more robust products that deliver their intended performance when either planned or unplanned changes are introduced. 

PTE: Priority 3 in the strategic plan also calls for developing new analytical methods, including those to determine 'similarity' between reference products and biosimilars as well as tools to detect physical properties of complex dosage forms. What gains are hoped for amongst agency scientists in these analytical areas? 

 Advances in analytical methods to determine 'similarity' between reference products and biosimilars, as well as tools to detect physical properties of complex dosage forms, will allow for greater confidence that there are no structural differences between products or that any differences observed are minor. For biosimilars, this will reduce uncertainty and allow for a targeted development program. This can also facilitate the development and approval of generics with complex dosage forms, as well as inform control strategies for quality of complex originator products. 

PTE: Priority 3 of the August 2011 strategic plan calls for reducing microbial contamination of medical products. What specific goals does FDA have in this area?

 FDA has attempted to identify and study specific gaps in pharmaceutical manufacturing. Studies are ongoing on sterilising filtration, effects of terminal- sterilisation energies on classes of products, and methods for detection of elusive microorganisms in drug components and manufacturing environments.   

Filtration studies have included microbial penetration rates based on the cell's size and filter matrix composition as well as penetration due to time on various filters with two sizes of growing microorganisms. The goal of these studies is to improve filter-validation studies that previously were shown to have vulnerabilities. Future steps in the research will look into solution conditions that encourage miniaturisation of the cells, neutralise cells or filter surface charges that enhance cell entrapment on filter membranes. 

Many products are manufactured using aseptic processing, which may be less effective than terminal sterilisation. Some other surgical products are not manufactured to be sterile at all, also posing risk. Each of these situations is the result of risk assessments that are based on the nature of the product and its vulnerability to sterilising energy or other conditions. FDA and NIPTE [National Institute for Pharmaceutical Technology and Education] have initiated studies of products (the initial focus is surgical antiseptics) to assess the effects of sterilising energy on selected products. The goal of these studies is to define conditions that may allow manufacturing to use processes intended to produce a sterile product, which is safer for use in surgical procedures. 

Nonsterile products often require a demonstration that microorganisms, normally expected to be in the product, will not grow or are killed. A similar demonstration is expected of sterile products that may be used several times (e.g., multidose vials). However, there exist microbial strains that can resist preservatives used to control contamination and some of these strains even grow in the presence of the antimicrobial agents. If allowed to grow, large numbers of microorganisms may reach a potentially infectious dose upon exposure to patients. Among these species are common water bacteria that CDC [Centres for Disease Control and Prevention] have shown to be difficult to detect using compendial methods. In collaboration with CDC and with help from the University of Michigan [US], we are examining culture methods for recovering these organisms from pharmaceutical water and products. Alternative technologies for their detection are also being considered. The goal of these studies is the development of methods to reliably detect these potential contaminants.  

PTE: One way to improve regulatory science (from a drug review standpoint) is to work with the industry directly to identify and fill in scientific and technological gaps that exist across drug development and manufacturing. FDA has created a few grant-based CERSIs, specifically with Georgetown University (GU) [US], the University of Maryland (UMD) [US], and the State of Arkansas [US]. Will the agency be opening any additional centres of excellence?

 We hope in future to fund one to two additional CERSIs, outside the region, but if and when depends on availability of funding. 

PTE: Can you comment on the staff training workshops held to date with these centres and their benefit to agency reviewers?

 Agency reviewers have had the opportunity to participate in training events sponsored by both UMD and GU CERSIs. These events have provided continuing medical education to staff and opportunities to network with leading researchers from around the country [US]. Additionally, agency reviewers have also had the opportunity to maintain their scientific and medical skills by participating in clinical work, research or teaching opportunities at UMD and GU CERSI.  

PTE: Section 1124 of FDASIA states that the US HHS Secretary should have a strategy and implementation plan 'for advancing regulatory science for medical products in order to promote the public health and advance innovation in regulatory decision-making' by July 2013. What is FDA's role? 

 FDA is taking the lead in developing the Strategy and Implementation Plan for Medical Products, as required in Section 1124 of FDASIA. 

PTE: Are any additional major goals expected beyond FDA's current strategic plan surrounding regulatory science?

 No, FDA expects to stay within the framework outlined in the Strategic Plan for Regulatory Science. The major areas of focus outlined in the Strategic Plan for Regulatory Science identify broad areas where advances in regulatory science are needed and are thus quite comprehensive. It is expected that the annual progress reports, which will follow in 2014 and 2016, will include more detailed information on specific accomplishments related to regulatory science. 

PTE: Part of FDASIA helps to fund FDA foreign inspections through new user fees (i.e., the Generic Drug User Fee Amendments of 2012 [GDUFA]). Starting in 2014, inspections will use risk-based methodologies. What factors will the agency use to determine whether and when to inspect a foreign facility?

 We have yet to finalise the revised risk-based approach although FDASIA Section 705 outlines the factors relevant to evaluating risk. All facilities will be inspected sooner or later. Firms new to FDA will be a priority as would be firms that are seeking approval for a type of manufacturing operation that is new to that site. FDA will consider establishing different frequencies for active ingredient and finished-dosage form production facilities. Facilities that make sterile drugs will likely be a higher priority than other types of production. GDUFA expects the frequency and rigor of domestic and foreign facility inspections to be equitable, which makes good sense for all drugs, so the risk-based model will have to ensure this is achieved. 

PTE: FDASIA calls for the agency to issue guidance by July 2013 that defines when an inspection may be denied or limited. What is the status? 

 As required by Section 707 of FDASIA, FDA is currently working on a draft guidance that will address the scope of actions or inactions that constitute a delay, denial, refusal or limitation of an inspection. Section 707 deems a drug misbranded if it is produced in a facility for which an inspection is delayed, denied, refused or limited. This provision is important because it creates a strong incentive for all facilities, including foreign facilities, to allow FDA to conduct timely and complete inspections. If a domestic facility delays, denies, refuses or limits an inspection, FDA has jurisdiction to obtain an inspectional warrant. Prior to FDASIA, however, FDA did not have an effective tool to facilitate the cooperation of foreign facilities with inspections. Now, if a foreign facility delays, denies, limits or refuses an inspection, FDA may refuse entry for all drug products produced in that facility. This will save FDA time and resources and help ensure the safety of our drug supply.  

PTE: FDASIA allows for FDA to use inspection information from other governments and agencies. Can you elaborate on this and other information-sharing?

 FDA inspection reports are generally detailed accounts of each inspection that include the purpose, description of the breadth and depth of coverage, findings and significant discussions with a firm's staff. FDA would be able to make use of comparably detailed reports from our counterparts and, under FDASIA Section 712, FDA would be able to recognise a foreign government's inspections once a review and audit of its system verifies its inspections to the satisfaction of FDA. FDA currently shares inspection reports, as well as data-systems access with counterpart national regulatory agencies that often use these reports or inspection findings in lieu of their own inspection. Fortunately, there now exists an organisation of pharmaceutical inspectorates that harmonises drug-regulatory practices: the Pharmaceutical Inspection Co-operation Scheme (PIC/S). FDA became a member of PIC/S approximately two years ago. Membership gives FDA an opportunity to work with fellow PIC/S member authorities to ensure that inspection standards are robust and followed. 

PTE: Regarding imports, FDASIA notes that foreign manufacturers must demonstrate the regulatory status of their drug as well as cGMP compliance and prove facility registration within the US; otherwise, the agency has the right to destroy noncompliant imported drugs under a $2500 value. These rules are set to take place in July 2014 after further regulations are developed. How will the new standards differ from current import and foreign registration requirements? 

FDASIA provides FDA clear authority to require information about drugs offered for import and to refuse admission if it is not provided, which strengthens FDA's ability to monitor imported drugs for compliance with applicable laws. Similar to many other countries, FDASIA places the burden on the importer or product owner to prove its drug complies with applicable US requirements. These import authorities strengthen FDA's ability to evaluate imported drugs for compliance with US laws and regulations. The authorities also enable FDA to better target higher risk products and prevent violative products from entering the US. 

FDASIA also grants FDA explicit authority to destroy violative drugs refused admission to the US if they are valued at $2500 or less. Before FDASIA's enactment, FDA had no independent administrative destruction authority. Instead, FDA could only issue a 'notice of refusal of admission' for noncompliant drugs offered for import. Once FDA issued a 'notice of refusal of admission', FDA had to rely on Customs and Border Protection (CBP) to either export or destroy the noncompliant import under the Tariff Act (19 U.S.C. 1595). By granting FDA administrative destruction authority after adequate notice and hearing, for violative drugs valued at $2500 or less, these new FDASIA authorities will not only create efficiencies and transparency in the import process, but also strengthen FDA's ability to protect public health. 

PTE: How will these new requirements affect the supply chain and drug shortages?

The new drug-safety authorities FDASIA grants FDA reflect a more comprehensive and transparent view of the drug supply chain. For instance, FDASIA Section 714 requires that commercial importers register with FDA and Section 703 requires that drug-product listings identify excipient information. By granting FDA new authorities that more accurately reflect the entire drug lifecycle, FDASIA better equips the agency to protect public health and minimise consumer exposure to unsafe, ineffective and poor quality drugs in today's globalised supply chain. FDA will continue all efforts to address and prevent drug shortages while implementing these new requirements, which are anticipated to further strengthen efforts to assure the safety and quality of drugs for US patients. 

Where are CMOs headed? A Q&A with DSM Pharmaceutical Products CEO Alexander Wessels by Angie Drakulich

DSM Pharmaceutical Products received an award for best CMO in the summer of 2013 from the second annual BioPharma Asia Industry Awards in Singapore. 

discussed industry trends in pharmaceutical outsourcing with DSM Pharmaceutical Products CEO Alexander Wessels. 

DSM Pharmaceutical Products CEO Alexander Wessels			

In your experience, what capabilities are CMOs now expected to have that they didn't have 5 or 10 years ago?

 DSM's stake in the pharma outsourcing market is based on a global portfolio of resources to continuously serve changing customer needs and bring real value as the pharma industry shifts business models. This requires a breadth and depth of expertise in the various areas of pharmaceutical technology that can be applied to customer challenges for increasingly efficient processes. We are embedding such innovations across our mammalian, microbial, chemical and finished dosage platforms. In the area of process analytical technology (PAT), for example, DSM has demonstrated the efficiencies and safety of microreactor technology for the commercialscale production of APIs as an example of process intensification to achieve more efficient commercial production, better manage manufacturing volumes and drive down total costs. In this way, we can challenge current process technologies with innovations in process intensification for next-generation manufacturing solutions.  

Cover Story

FDA talks about the changing scope of regulatory science and its effect on drug reviews, site inspections, overall approaches.

A Look Ahead at Manufacturing and Regulation

Ray O'Connor, Operations Consultant, at the National Institute for Bioprocessing Research and Training (NIBRT) discusses the basics of biopharmaceutical facility design and operation. NIBRT provides training, educational and research solutions for the international bioprocessing industry in state-of-the-art facilities. Located in South Dublin (Ireland), it is based on an innovative collaboration between University College Dublin, Trinity College Dublin, Dublin City University and the Institute of Technology Sligo.  

Q  PTE: Why is aseptic processing crucial for injectables, such as vaccines and other biologic-based products?

Certain pharmaceutical products must be sterile as they're introduced to the patient by injection because this mode of drug delivery bypasses the body's natural defences. Therefore, with biologics, there is an increased risk of infection being introduced to the patient. Sterile drug products can be manufactured using two techniques: terminal sterilisation or true aseptic processing. Terminal sterilisation usually involves heat or irradiation; however, quite a large proportion of vaccines and biological-based drugs can be destroyed by exposure to heat or irradiation; hence, the requirement to manufacture in an aseptic manner. 

According to the FDA's guidance for industry on sterilised drug products produced by aseptic processing issued in September 2004, in an aseptic process, the drug product and container–closure are subjected to sterilisation methods separately, as appropriate, and then brought together. Because there is no process to sterilise the product in its final container, it is crucial the containers be filled and sealed in an extremely high-quality environment. Therefore, aseptic processing involves more variables than just terminal sterilisation. Before aseptic assembly into a final product, the individual parts of the final product must be subjected to various sterilisation processes. 

Similarly, in the EU, GMP guidelines state that the manufacture of sterile products is subject to special requirements to minimise the risk of microbial contamination and of particulate and pyrogen contaminant. So, as a result, much of the aseptic process depends on the scale of training and attitudes of the people involved. 

It's particularly important that this type of manufacture strictly follow established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects would not be placed on any terminal process or finished product testing. To summarise, aseptic processing is minimising the risk of introducing any microbial contaminant into your product as you move it through the manufacturing process. 

Q  PTE: Aseptic processing and the term 'fill–finish' are often used interchangeably throughout the industry. Are these two terms truly the same or are there unique steps for each?

 Fill–finish is a discrete part of the manufacturing process. If you have an upstream or downstream process, that will be where you manufacture your active ingredient. Fill–finish is the filling and packaging part of this process. It comes after the product has been manufactured and is ready to be put into its final package container that the patient will see. 

Aseptic processing refers to the various techniques that go into ensuring that the product is free of contaminants, thereby reducing the risk of infection to the patient. Aseptic processing is the processing of drug components, drug product containers and excipients in a manner that precludes microbial contamination of the final sealed product. 

Q  PTE: What types of product contamination can occur during bioprocessing?

Contamination in the biopharmaceutical industry can have serious health effects on the patient, so it is crucial to monitor and avoid. The different types of contamination one might find include bacteria, which could cause an infection in someone who is already ill, thus making the actual condition worse; chemicals, which could cause poisoning or other effects on the patient; and physical contamination, which could be particulates that can cause serious problems, such as cuts, blockage or even death in the patient. If work is being done in a multiproduct facility, cross-contamination from one product to another can occur as well.  

With regard to bacteria, viable particles are of particular concern in the biopharmaceutical industry. If they enter a product, they will multiply rapidly (e.g., they can double in under 20 min in the right conditions). If bacteria get into the system, they can actually overpower the product being made and you may end up losing the product. 

Most bacterial contamination comes from human beings. Hence, it's vitally important that when staff walk into a cleanroom or work in a cleanroom, they must be appropriately garbed to ensure minimal exposure of skin to the environment. 

Overall, there are five main routes of entry into the product of any type of contaminant. First is raw materials. All the raw materials used in the manufacturing of the product are potential sources of contamination. Quality systems associated with the supply and release of raw materials into the manufacturing processes are critical. A second source is the plant. Poorly sanitised equipment can lead to contamination. A third source is the environment. The cleanroom design, as described below, must be executed properly. Fourth is movement of personnel. It's important that people move in a controlled and deliberate fashion in a cleanroom. Erratic behaviour can generate particles. A fifth source is gowning. People represent 80–90% of common contamination sources. Proper gowning behaviour and training in aseptic technique and aseptic processing is vital. 

Q  PTE: What type of equipment is typically used for aseptic processing?

 The major piece of equipment, so to speak, is a cleanroom. Cleanrooms contain laminar airflow hoods, isolators or restricted access barrier systems (RABS), filling lines, sterilising filters, autoclaves for sterilising the equipment, depyrogenation tunnels for removing any endotoxins, as well as other equipment. Cleanrooms also have automated cleaning systems for reducing any low levels of contaminants prior to sterilising and isolators that have filling lines installed in them. These units are totally enclosed and have a localised area with what's called "Grade-A air" inside of them; this is where the filling line fills the product into final containers such as vials, syringes or bags.  

A cleanroom could also have various environmental monitoring devices; filters, which are important for removing contaminants; and finally, single-use disposable systems, which are becoming more prevalent these days. 

Q  PTE: Can you provide more details about cleanrooms and the garments that are required?

There are a number of different standards around cleanrooms, but the International Organisation for Standardisation (ISO) 14644-1 defines a cleanroom as a room in which the concentration of airborne particles is controlled and which is constructed and used in a manner to minimise the introduction, generation and retention of particles inside the room and which other relevant parameters (e.g., temperature, humidity and pressure) are controlled as necessary. 

Within the cleanroom, the critical components include high-efficiency particulate air filters on the ceilings that filter all the air coming into the room, as well as exhaust vents at the floor level. These vents ensure that laminar airflow and effective removal of air so that there are many air changes per hour, typically from 5 to 100. There should not be any drains inside an aseptic processing area in a cleanroom. Airlocks are important to facilitate the movement of people and equipment from one cleanroom into another. 

It's important that cleanrooms are designed appropriately to ensure seamless and rounded floor-to-wall junctions to prevent buildup of any contamination or water. Floors and walls and ceilings must be constructed of smooth, hard surfaces that can be easily cleaned. One should limit the amount of fixtures and fittings on the walls to facilitate the ease of cleaning of walls, and layout of equipment must be optimised for the comfort, and movement of people.  

In addition to ISO 14644, in Europe, cleanroom classifications are divided into Class A, B, C and D, where A is the most stringent and D is the least exacting. In the US, room classifications are referred to as Class 100, Class 1000, Class 10,000 and Class 100,000. The ISO standards then would be 5, 6, 7 and 8. The standards in general apply to particle sizes in the range of 0.5 microns to 5 microns. 

The standards are used interchangeably, depending on where your site is located and where you're being regulated. So, if your site is regulated by FDA, it would use the Class 100, 10,000, 100,000 standards. Similarly, if your site follows the European standard, that means using Class A, B, C and D. A Class-A air area would be used to perform a high-risk operation such as filling or making aseptic connections. A Grade-B area is typically used for aseptic preparation and as a background environment for traditional filling operation. Grade C is used for preparation of solutions and equipment. 

Microbial monitoring is also required to demonstrate the cleanliness of the cleanroom during production. The recommended limits are specific for the each room classification. Cleanrooms should have settle plates where air is allowed to settle to support the growth of bacteria. Staff can then see how much bacteria might be in the environment. Contact plates can be put up against walls and surfaces, and gloveprints can be used in Grade A and B areas. Gloveprints are where people actually place their gloved fingers to see whether there is any contamination present. 

With each area, there are standardised limits. In a Grade-B room, for example, one can have no more than 10 colony forming units. It's important to trend these results, otherwise one cannot determine whether the room is under control. If there is no control, the product is at risk. 

Q  PTE: What sort of environmental monitoring program need to be used in aseptic processing?

The goal of an environmental monitoring program is to provide meaningful information on the quality of the aseptic processing. Typical controls are for airborne particles and nonviable contaminant monitoring (i.e., to analyse the amount of microbes in the room). Viable contaminant monitoring of surfaces involves touching surfaces with agar plates. Viable monitoring of personnel and temperature–humidity monitoring are also typical controls to have in place. 

Environmental monitoring must be done across all processing shifts (i.e., day and night). All floors, walls and equipment surfaces need to be tested. The location of the surfaces to be sampled, and the timing and frequency of the sampling, should be specified in writing, so that it is not just a random process, but rather, a risk-based process. It's also important for staff to ensure reproducible results. 

The heating and ventilation and air conditioning (HVAC) unit should be under control of the building management system. This system controls the amount of air coming in to the cleanrooms and the differential pressure across the HEPA filters. If any changes are observed, actions and alerts should be raised to start an investigation and corrective–preventive action plan.  

Q  PTE: Various analytics and testing are involved in aseptic processing, including sampling, validation, and identification. Can you talk about some of the major considerations manufacturers need to keep in mind for this part of aseptic processing?

 Sampling is an important part that involves testing to determine whether your process is in control throughout manufacturing. Before approving a process, it must be validated, which requires an extensive battery of tests on the product, including characterisation, identification, and contamination minimisation. One key factor for taking samples of biologics is to ensure that the product is not contaminated while samples are taken, which could lead to false positives. 			

Samples are also taken after the product has been sterile-filtered for sterility testing. If the product does not pass sterility test, it will be a failed batch and will be rejected.  

Aseptic

PharmTech speaks to Ray O'Connor from the National Institute for Bioprocessing Research and Training (NIBRT) for an overview of aseptic processing.

Aseptic Processing: A Primer

In 2008, a report published by an economics professor at Johns Hopkins University, in partnership with the Association of British Pharmaceutical Industry and the UK Vaccines Industry Group, predicted that the vaccines sector had the potential to enter a new golden era (1). The early part of the 20

  century had seen vaccines play a major role in combatting infectious diseases, but since the 1970s, cost pressures, mergers between companies, production setbacks and a series of high-profile liability cases have led to many manufacturers abandoning this area in favour of more profitable alternatives.  

The potential for manufacturing issues to severely disrupt operations remains a constant headache for vaccine manufacturers. In Europe, several major manufacturers experienced such problems during 2012.  

In October 2012, several EU member states suspended the use of some anti-influenza vaccines manufactured by Novartis because of suspected quality defects. Although there was no evidence of the problems impacting efficacy and safety, the authorities acted as a precautionary measure. The Italian Medicines Agency was the first to act over Novartis' Aggripal, Fluad and Influpozzi products when it received a verbal notification from Novartis. The agency subsequently warned other member states, the European Commission and the European Medicines Agency (EMA). Although Novartis provided the Italian authorities with data it believed supported the high quality, efficacy and safety of their products, other countries followed Italy's lead in banning the products (2–5). Reports of protein particulates in some vials were enough to persuade France, Austria, Germany, Spain and Switzerland to act. Canada and Singapore also followed suit. 			

According to Novartis, the particulates reported in the vials were all "normal and necessary components" of their influenza vaccines and that the aggregation of these proteins was not considered unusual in terms of vaccines manufacturing (6). Furthermore, Novartis stated that clinical data demonstrated similar safety and immunogenicity profiles to prior years for these products. Additional data from the ongoing seasonal vaccination campaign in Europe had also not revealed any safety signals. Nevertheless, the Italian authorities sought an explanation from Novartis as to why it had taken until October to inform them of the particulate issues, despite the company identifying such problems in July (7).  

The manufacturing issues have not only proven to be damaging to Novartis' reputation, but may also represent a new financial setback for the company's vaccines unit. The unit has been underperforming financially since 2010, when it had revenues of $2.9 billion (2). In 2011, reports claimed that the company had made a $249 million operating loss on $2 billion in revenue. The 2012 manufacturing issues will inevitably dampen prospects of surpassing 2010's revenue. 

The influenza vaccine manufacturing issue has led to concerns that there will be a shortage of influenza vaccines this coming winter in the UK, Germany, Switzerland and Italy, although most governments should have alternative sources and strategic reserves in place. Germany, for example, has turned to GlaxoSmithKline and Abbott to help make up any shortfall, and predictions from the German Health Ministry suggest that the number of available flu vaccines available in Germany will be 14 million, which is comparable to 2011 (5). Despite these reassurances, disruptions tend to cause controversy between governments, pharmaceutical companies and healthcare professionals about why vaccine shortages occur in the first place. With respect to the situation in Germany, pharmaceutical companies and some physicians have blamed insurance companies, whom they claim negotiate exclusive contracts with vaccine manufacturers in exchange for better rates, which puts patients at risk (5). 

In October 2012, Crucell, which is based in the Netherlands and provides approximately 10% of the UK's influenza vaccine stock, halted production after discovering problems with two of its product batches. The company has stated that it is continuing to conduct quality tests before releasing any more vaccine, although it has not recalled any of the stocks that have already been distributed. The manufacturing issues at Crucell are particularly frustrating for Johnson & Johnson, which finalised acquisition of the company in 2011 for $2.4 billion, with the aim of accessing the global vaccines market. The acquisition was Johnson & Johnson's largest since 2006, when it took over Pfizer's consumer unit for $16.6 billion. For now, Johnson & Johnson will be preoccupied with resolving the manufacturing issues and reassuring their existing vaccine clients before the company can pursue its intended ambitious growth plans in the sector. 

Another company that has recently suffered vaccine manufacturing issues, although not for anti-influenza products, is GlaxoSmithKline. In October 2012, the company cooperated with Australia's Therapeutic Goods Administration for a voluntarily recall of six batches of Infanrix hexa, a vaccine product used to prevent diphtheria, tetanus, pertussis (whooping cough), hepatitis B, poliomyelitis (polio) and Haemophilus influenzae type b (Hib). Testing had revealed low-level contamination in certain batches dispatched between August 2011 and January 2012, although the company stressed that no reported adverse events had been directly linked to this issue. Later in October, the company recalled a single lot of the same vaccine in Canada, citing potential microbial contamination, but continuing to state that it was purely a precautionary measure (8). In November 2012, GlaxoSmithKline confirmed that the affected batches had originated from its plant in Rixensart, Belgium (9). Potential microbiological contamination had been identified in the environment where bulk antigens for some of its Infanrix Hexa, Infanrix-IPV and Infanrix- IPV/Hib vaccines were placed, but release tests (including sterility tests) on intermediates and on the final containers led to the conclusion that the final products released from the facility had not been contaminated (8). The company continues to resolve the issue, but the recall of these products may have an impact in up to 20 countries. As well as many EU Member States, countries such as Lebanon, Malaysia, Qatar, Brazil and Vietnam may be affected by short supplies of the vaccine (9). 

Vaccines are essential to combat a range of disease threats and the migration of companies out of the sector has worried health agencies worldwide. Efforts have been made to stimulate renewed industry interest and persuade companies that it is an ideal opportunity for them to harness scientific advances made in genetics and biotechnology. There are signs that these factors are persuading some companies to increase their activities in the vaccines sector, but as recent experience shows, manufacturers face considerable technical challenges. After a troublesome last quarter of 2012, Novartis now appears to be on the verge of resolving the manufacturing issues it has faced with its influenza vaccines. Canada and Switzerland lifted their bans in late October, followed by Singapore and then Italy in the first part of November. However, the company still needs to work with authorities in other countries to allow supplies to resume. For other companies, such as Crucell and GlaxoSmithKline, efforts to restore confidence in their vaccine expertise look likely to continue through 2013. 

What are the Prospects for a New Golden Era in Vaccines?

 Pharmaletter website, "Novartis' flu vaccines suspended in several countries on suspected quality issues", 

 Fiercepharma website, "Italy bans Novartis vaccines even after company assures their safety", 

 Reuters website, "France halts sale of Novartis flu vaccine", 

 Deutsche Welle website, "Germany moves to cut off vaccine shortage", 

 The Globe and Mail website, "Canada suspends distribution of Novartis flu shots", 

 Fiercepharma website, "Novartis plant delay, vaccine woes steal spotlight", 

 Health Canada website, "Health Canada Endorsed Important Safety Information on Infanrix Hexa", 

 In-pharmatechnologist website, "GSK pulls vaccine batch in Canada over contamination concerns", 

Industry Insider

Vaccine manufacturing was predicted in 2008 to be on the cusp of a golden era, but instead the industry has experienced cost pressures, high-profile liability cases and production setbacks.

Manufacturing Misery in Vaccines

THE LATEST IN AUTOMATION/IT/PROCESS CONTROL

Optical absorption sensor detects product loss

Sparta Systems has enhanced the audit capabilities of its TrackWise Enterprise Quality Management System. The Audit Execution Package includes a Solution Delivery Analyst to help create a customised deployment plan to accelerate user adoption and a Subject Matter Expert to train end users with the knowledge necessary to adhere to industry regulations. The package enables users to streamline auditing processes by creating tailored templates, as well as a scorecard to evaluate system effectiveness. Off-line capabilities include the ability to document results in real time that can be directly exported to provide data for tracking and trending. Auditors can also electronically send audit observations to suppliers and import responses directly into the TrackWise system. 

Data acquisition station saves data for longer time periods

The GX and GP data-acquisition stations and GA10 software are the first members of Yokogawa's all-new SMARTDAC+ product family that incorporates Smart User Interface, Smart Architecture and Smart Functionality design principles. The stations contain applications that are designed to measure more input signals, save data for longer time periods and access that data more readily via touch display screens and a real-time, web-browser interface. 

The stations feature new modular I/O architecture that allows the user to add input channels and alarm relays in any combination and at any time, simply by purchasing the required module(s) and installing them in rear panel slots. A 10-channel universal input module supports a full range of thermocouple, RTD and DCV sensor measurements, as well as mA inputs with external shunt resistors. 

					Contact company for availability information

Probe enables monitoring of in-process vacuum

Hiden Analytical's in-process vacuum monitor, the HALO 201 MBE, was initially designed for application to the molecular beam epitaxy process and is suitable for use in difficult process conditions. Many vacuum-related processes operate at high- or ultra-high vacuum levels that represent a difficult environment for quadrupole mass spectrometers, but the sensitive ionisation region of the HALO 201 MBE probe is completely shrouded to inhibit random surface deposition. With a mass range of 1–200 amu, the probe can be used for measuring all common gasses and contaminants, and features operating modes for vacuum species identification, leak detection, and process trend analysis. 

Pressure transmitter for efficient manufacturing processes

Honeywell's SmartLine industrial pressure transmitters are designed to enhance communication abilities, improve operational efficiency and reduce lifecycle costs for process manufacturers. The transmitters are intended to make it easier to support field devices and promote plant reliability with their efficiency-enhancing features, such as a graphic display capable of showing process data in graphical formats and communicating messages from the control room. SmartLine transmitters also feature modular components to simplify field repairs and reduce inventory required to make such repairs. 

					Transmitters are available worldwide

Product Spotlight

Editor's Picks of Pharmaceutical Science & Technology Innovations

Issue PDF

Click the title above to open the Pharmaceutical Technology Europe January 2013 issue in an interactive PDF format.

Pharmaceutical Technology Europe-01-01-2013

Pharma Never Dies

A Look Ahead at Manufacturing and Regulation

Aseptic Processing: A Primer

Manufacturing Misery in Vaccines

Product Spotlight

Pharmaceutical Technology Europe, January 2013 Issue (PDF)